Bis(n-haloalkanoyl-piperidyl)alkanes and bis[n-(haloalkanoyl-aminoalkyl)-piperidy]alkanes



United States Patent BIS(N HALOALKANOYL PIPERIDYL)ALKANES ANDBIS[N-(HALOALKANOYL AMINOALKYL)- PIPERIDYL1ALKANES Alexander R. Surrey,Albany, N.Y., assignor to Sterling Drug Inc., New York, N.Y., acorporation of Delaware No Drawing. Filed Oct. 17, 1963, Ser. No.317,079 8 Claims. (Cl. 260294) This invention relates to compositions ofmatter of the class of substituted piperidines.

The invention here resides in the concept of a composition of themolecular structure in which alkylene having from three to eight carbonatoms between its connecting linkages is attached through each of itstwo connecting linkages to a carbon atom of a piperidine ring bearing asan N-substituent halo-lower-alkanoyl attached directly or throughaminoalkyl having from two to six carbon atoms. The N-substituents ofthe two piperidine rings can be the same or different and the points ofattachment of the alkylene moiety to the piperidine ringcarbon atoms canbe at any available position, e.g., 2, 3 or 4, and can be the same ordifferent for the two piperidine rings.

The physical embodiments of the. concept have been tested by standardchemotherapeutic evaluation procedures in vivo in hamsters and found topossess amebacida-l activity.

Among the compounds of my invention are the dipiperidines of the FormulaI where Ac and Ac are each halo-lower-alkanoy1 having from one to fourcarbon atoms and from one to three halogen atoms, Y is alkylene havingfrom three to eight carbon atoms between its connecting linkages, X andX are each alkylene having from two to six carbon atoms and having atleast two carbon atoms between its connecting linkages. Optionally, eachpiperidine ring can be substituted by lower-alkyl radicals, e.g.,methyl, ethyl, n-propyl, and the like, at available ring-carbonpositions.

In the above Formulas I and II, Y represents alkylene having from threeto eight carbon atoms between its connecting linkages, illustrated byz)1, 2)r-, CH(C2H5) (cumand the like.

In the above Formula II, X and X can be the same or different and eachhas from two to six carbon atoms and has at least two carbon atomsbetween its connecting linkages, illustrated by Optionally, the abovealkylene radicals represented by Y, X and X can be interrupted by O, Sand carbonto-carbon double bonds provided the O, S or double bond is notdirectly attached to either of the terminal carbon. atoms bearing theconnecting linkages, e.g.,

-CH CH CH=CHCH and the like.

In the above Formulas I and H, the halo-loweralkanoyl radicalsdesignated as Ac, and A0 can be the same or different and each can havepreferably from one to four carbon atoms and from one to three halogenatoms, as illustrated by chloroformyl (ch-loromethanoyl), chloroacetyl(chloroethanoyl), bromoacetyl, iodoacetyl, fluoroaoetyl,dichloroace-tyl, dibromoacetyl, diidoacetyl, difluoroacetyl,bromochloroacetyl, chlorofluoroacetyl, trichloroacetyl, tribromoacetyl,bromodichloroacetyl, chlorodibromoacetyl, dichlorofiuoroacetyl,chloroiodoacetyl, 2-chloropropanoyl (alpha-chloropropionyl),3-chloropropanoyl (beta-chloropropionyl), 2-bromopr-opanoyl,2,2-dichlor-opropanoyl, 2,2-diiodopropanoyl, 2,2-dibromopropanoyl,2,2-difluoropropanoyl, 2,3-dichloropropanoyl, 2-bromo-3-chloropropanoyl,2,2,3-trichloropropanoyl, 2- chlorobutanoyl (alpha-chlorobutyryl),3-chlorobutanoyl, 4-chlorobutanoyl, 2,2-dichlorobutanoyl,2,3-dibromobutanoyl, 2,2-dibromobutanoyl, 2,3,4-trichlorobutanoyl,2,2,3-tribromobutanoyl, and the like.

The N,N-di-(halo-lower-alkanoyil)-diamines of Formulas I and H where thehalo-lower-alkanoyl substituents are the same are prepared by reacting,respectively, the corresponding diamine of Formula III l H E where Y ineach of Formulas III and IV has the meaning given above for Formulas Iand II and where X and X are defined as above for Formula II, with twomolar equivalent quantities of a halo-lower-alkanoylating agent derivedfrom an acid of the formula Ae -OH. Found particularly useful ashalo-lower-alkanoy-lating agents were halo-alkanoyl halides of theformula Ac -halogen and lower-alkyl halo-alkanoates of the formula Ac O-(loWer-a-lkyl) where Ac has the meaning given above for Formulas I andII and the lower-alkyl portion of the ester is preferably methyl, but,can have from one to six carbon atoms, e.g., ethyl, isobutyl, n-hexyl,and the like. The halo radical attached to the carbonyl of the acylhalide is preferably chloro; however, other halo radicals, i.e., *bromo,iodo or fluoro, also can be used.

When a halo-lower-alkanoyl halide is used as the halo-acylating agent,the reaction is carried out preferably below room temperature, e.g.,between 010 C., and preferably in the presence of an acid acceptor,e.g., NaOH, triethylamine, etc., to take up the hydrogen halide formedby the reaction. The halo-alkanoyl halides are preferred acylatingagents, in particular, in the reaction with the compounds of FormulaIII.

When a 1ower-alkyl halo-lower-alk-anoate is used as the halo-acylatingagent, the reaction is run at room tem- 3 perature or by warming thereactants, if necessary, at a temperature of about 50 to 100 C.

In the preparation of a di-(chloroformamide), i.e., where A ischloroformyl, the di-piperidine, preferably as its dihydrochloride isreacted with phosgene while suspended in a nonpolar solvent, e.g.,toluene, as illustrated by the preparation of 1,6-bis(N-chloroformyl-Z-piperidyl) hexane or1,6-bis'[N(2-chloroformamidoethyl)-2-piperidylJhexane by bubblingphosgene into a stirred refluxing suspension of 1,6-bis(2-piperidyl)hexane or 1,6-bis [N-(2 aminoethyD-Z-piperidyl] hexane, respectively.

The N,'-N-di-(halo-.alkanoyl)-diamines of Formulas I and II where thehalo-alkanoyl substituents are difierent are prepared stepwise by firstreacting the diamine of Formula IE1 or IV with one molar equivalent ofone haloalkanoylating agent and then reacting the resulting monoacylatedcompound with one molar equivalent of a different halo-alkanoylatingagent.

The intermediate bis(piperidyl) alkanes of Formula III are generallyknown compounds which are readily prepared by known procedures. Theintermediate bis(N- aminoalkylpiperidyl) alkanes of Formula IV are novelcompounds which are prepared by the procedure described hereinbelow inthe specific exemplary disclosure.

The chemical structures of my novel compounds are established by themodes of syntheses and corroborated by the correspondence of calculatedand found values for elemental analyses for representative examples.

The following examples will further illustrate specific embodiments ofthe invention without, however, limiting it thereto.

Example 1 1,6-bis(N-dichcloroacetyl-2-piperidyl)hexane: A solutioncontaining 12.6 g. of 1,6-bis(2-piperidyl)hexane and 150 cc. of ethylenedichloride was cooled in an ice bath to 0 C. and to this solution wasadded dropwise, keeping the temperature below 5 C. during addition, asolution containing 17.6 g. of dichloroacetyl chloride in 50 cc. ofethylene dichloride and suflicient aqueous sodium hydroxide solution tokeep the reaction mixture basic. After the addition had been completed,the reaction mixture was stirred for one hour in the ice bath and thenfor an additional hour at room temperature. The layers were separated;the ethylene dichloride layer was washed successively with diluteaqueous hydrochloric acid, sodium bicarbonate solution and water; it wasthen dried over anhydrous sodium sulfate, filtered, and concentrated invacuo to remove the solvent. The residual material was dissolved inbenzene and the resulting solution then passed through a column (2 cm.by 50 cm.) of an activated magnesium silicate (Florisil). The resultingsolution was concentrated in vacuo to remove the solvent and theresidual material dried in vacuo (0.5 mm.) with warming for about threehours and then cooled to yield a solid material. A small quantity of thesolid was triturated with ethyl acetate to yield a white solid. Theremainder of the solid was dissolved in hot ethyl acetate, the seedcrystals added and the mixture allowed to stand. The solid thatseparated was recrystallized from ethyl acetate to yield 5.9 g. of theproduct, 1,6-bis(=N-dich1oroacetyl-2- piperidyl)hexane, M.P.132.6-'137.8 C. (corn).

Analysis.Calcd. for C 'H Cl N O C, 50.63; H, 6.80; CI, 29.90. Found: C,50.95; H, 7.12; Cl, 29.55.

1,6-bis(N-dichloroacetyl-2-piperidyl)hexane when administered orally tohamsters infected with Endamoeba criceti was found to have an ED of1.77:0.25 mg./ kg./day, ED meaning the effective dose necessary to clear50% of the hamsters of the amebic infection.

[Following the above procedure but substituting for dichloroacetylchloride molar equivalent quantities of dibromoacetyl bromide,diiodoacetyl chloride, difluor-oacetyl chloride, bromochloroacetylchloride, 2,2-dibromopropanoyl bromide, 2,3-dichloropropanoyl chloride,or 2,2-di- 4 chlorobutanoyl chloride, the following compounds areprepare-d:

1,6-bis (N-dibromoacetyl-Z-piperidyl) hexane,

1,6-bis (Ndiiodoacetyl-2-piperidyl) hexane,

1,6 'bis (-N -difluoroacetyl-2-piperidyl) hexane,

1,6-bis N-bromochloroacetyl-2-piperidyl hexane, 1,6-bis(N-2,2-dibromoprop anoyl-Z-piperidyl) hexane, 1,6-bis (N-2,3-dichloroprop anoyl-2-piperidyl) hexane or 1,6-bis(N-2,2-dichlorobutanoyl-2-pip eridyl hexane, respectively.

Following the above procedure but substituting for 1,6-bis(2-piperidyl)hexane molar equivalent quantities of 1,4-bis(2-piperidyl)=butane,

1,4-bis 2-piperidyl) hexane,

1 ,8-bis(2-piperidyl) octane,

1,6-bis 3-piperidyl) hexane, 1,6-bis(4-piperidyl) hexane,

1- (2-piperidyl) -6-(4-piperidyl)hexane, 1,6-bis 3,6-dimethyl-2-piperidyl) hexane or 1- (2-piperidyl) -6-( 3-piperidyl)hexane,

the following compounds are prepared:

1,4-bis (N-dichloroacetyl-2-piperidyl) butane,

1,4-bis (N dichloroacetyl-2-piperidyl)hexane,

1,8-bis (N -dichloroacetyl-Z-piperidyl)octane,

1,6-bis (N-dichloroacetyl-3piperidyl) hexane,

1,6-bis N-dichloroacetyl-4-piperidyl hexane,

1- (N-dichloroacetyl-Z-piperidyl) -6- (N-dichloroacetyl- 4-piperidyl)hexane,

1,6bis(N-dichloroacetyl-3 ,6 -dimethyl-2 -piperidyl) hexane or I 1-(N-dichloroacetyl-2-piperidyl) -6-(N-dich10r0acetyl- 3-piperidyl)hexane,

respectively.

Example 2 1,6-bis(N-chloroacetyl 2 piperidyl)hexane was pre paredfollowing the procedure described in Example 1 using 10.2 g. of1,6-bis(2-piperidyl)hexane in cc. of ethylene dichloride, 11.3 g. ofchloroacetyl chloride in 50 cc. of ethylene dichloride, and an excess of10% aqueous sodium hydroxide solution. The layers of the reactionmixture were separated. The ethylene dichloride layer was washedsuccessively with dilute aqueous hydrochloric acid and water; it wasthen concentrated in vacuo to remove the solvent whereupon there wasobtained a yellow oil which crystallized on standing. This material wastriturated with ethyl acetate and collected to yield 3.5 g. of theproduct, 1,6-bis(N-chloroacetyl-2-piperidyl) hexane, M. P. 87.09l.0 C.(corn).

Analysis-Calm. for C H Cl N O C, 59.25; H, 8.45; Cl, 17.49. Found: C,59.29; H, 8.23; Cl, 17.56.

1,6-bis(N-chloroacetyl-2-piperidyl)hexane when ad ministered orally tohamsters infected with Endamoeba criceti was found to have an ED of1.46:0.17 mg./kg./ day.

Following the above procedure but substituting for chloroacetyl chloridemolar equivalent quantities of bromoacetyl bromide, iodoacetyl chloride,fluoroacetyl chloride, 2-chloropropanoyl chloride, 2-bromopropanoylbromide, 3-chloropropanoyl chloride, 2-chlorobutanoyl chloride or4-chlorobutanoyl chloride, there are obtained the, I

following compounds:

1,6-bis (N-bromoacetyl-Z-piperidyl hexane,

1,6-bis (N-iodoacetyl-Z-piperidyl) hexane,

1,6-bis (N-flu-oroacetyl-2-piperidyl) hexane,l,6-bis(N-2-chloropropanoyl-2-piperidyl hexane,

1 ,6-bis (N-2-bromopropanoyl-Z-piperidyl hexane, 1,6-bis(N-3-chloropropanoyl-2-piperidyl) hexane, 1,6-bis(N-Z-chlorobutanoyl-Z-piperidyl) hexane or 1,6-bis(N-4-chlorobutanoyl-2-piperidyl hexane,

respectively.

Example 3 1,3-bis(N-dichloroacetyl-Z-piperidyl)propane: To a solutioncontaining 10.5 g. of 1,3-bis(N-2-piperidyl)propane, 10.1 g. oftriethylamine and 150 cc. of chloroform was added over a fifteen minuteperiod with stirring a solution containing 16.1 g. of dichloroacetylchloride in 50 cc. of chloroform. The reaction mixture was stirred forone hour at room temperature; washed successively with water, diluteaqueous hydrochloric acid, aqueous sodium bicarbonate solution andwater; and then concentrated in vacuo to yield an orange oily material.Thin layer chromatography (TLC) on silica gel plates showed four spotsin 80% chloroform-20% ether, I developer. A silica-gel column (150 g./502.5 cm.) was prepared using 80% chloroform-20% ether. Three 500 cc.fractions were collected and each concentrated in vacuo to remove thesolvent. The TLC plate on the first fraction showed it to be homogenous;on standing, the oil from this fraction crystallized and was thenrecrystallized from a minimum amount of ethyl acetate to yield 3.0 g. ofthe product, 1,3-bis(N-dichloroacety1- 2 piperidyl)propane, M.P.146.2148.0 C. (corn).

Analysis.Calcd, for C17H26CI4N2O2Z C, 47.24; H, 6.06; Cl, 32.82. Found:C, 47.32; H, 6.23; Cl, 33.18.

1,3-bis(N-dichloroacetyl-2-piperidyl)propane when administered orally tohamsters infected with Endamoeba criceti was found to have an ED of7.4122 mg./kg./ day.

Example 4 1,3-bis(N-chloroacetyl-2-piperidyl)propane was preparedfollowing the procedure described in Example 3 using 10.5 g. of1,3-bis(2-piperidyl)propane and 10.1 g. of triethylamine in 150 cc. ofchloroform, 12.4 g. of chloroacetyl chloride in 50 cc. of chloroform,and six 500 cc. fractions of 80% chloroform-20% ether in thechromatographic separation. The first three 500 cc. fractions werecombined and the solvent removed in vacuo with warming to yield 10.1 g.of the product, 1,3-bis(N-chloroacetyl-2-piperidyl)propane, a yellowoil, n =1.5288.

Analysis.Ca1cd. for C H Cl N O C, 56.20; H, 7.77; Cl, 19.52. Found: C,56.50; H, 7.84; Cl, 19.31.

1,3-bis(N-chloracetyl-2-piperidyl)propane when administered orally tohamsters infected with Endamoeba crz'ceti was found to clear 5 out of 5of the animals at a dose level of 25 mg./kg./day.

Example 5 1,6 bis[N (2 dichloroacetamidoethyl) 2 piperidyl]hexane wasprepared as follows: To 4.0 g. of 1,6-bis[N-(Z-aminoethyl)-2-piperidyl]hexane was added 3.5 g. of methyldichloroacetate whereupon an exothermic reaction took place. Thereaction mixture was cooled; the viscous oil that separated crystallizedand was collected. The crystalline material was recrystallized twicefrom isopropyl alcohol, using decolorizing charcoal each time, and driedat 60 C. at 20 mm. for eighteen hours to yield 4.1 g. of the product,1,6-bis[N-(2-dich1oroacetamidoethyl)-2-piperidyl]hexane, M.P. 104.4105.6C. (corn).

Analysisi.-Calcd. for C H Cl N O N, 9.99; CI, 25.31. Found: N, 10.07;Cl, 25.39.

1,6 bis[N (2 dichloroacetamidoethyl) 2 piperidyl]hexane whenadministered orally to hamsters infected with Endamoeba criceti wasfound to clear 4 out of 5 (75% corrected, controls 1 out of 5) at 25mg./kg./ day.

The above compound is also obtained by following the procedure ofExample 1 using l, 6-bis[N-(2-aminoethyl)- 2-piperidyl1hexane anddichloroacetyl chloride as the reactants. Using chloroacetyl chloride,trichloroacetyl chloride 2,2-dibromopropanoyl bromide or2,2-dichlorobutanoyl chloride in place of dichloroacetyl chlorideyields, respectively,

6 1 ,6-bis [N- 2-chloroacetamidoethyl) -2-piperidyl] hexane, 1,6-bis [N2-trichloro acetamidoethyl) -2- piperidyl] hexane, l,6-bis{N- [2-(2,2-dibromopropanamido)ethyl] -2- piperidyl}hexaue or 1,6-bis{N- [2-2,2-dichlorobutanamido) ethyl] -2- piperidyl}hexane.

The above intermediate 1,6-bis[N-(2-aminoethyl)-2- piperidy1]hexane wasprepared in two steps as follows: To 42.2 g. of1,6-bis(2-piperidyl)hexane was added slowly 30 g. of glycolonitrile(70%) whereupon an exothermic reaction took place. The reaction mixturewas allowed to stand for thirty minutes, heated on a steam bath for twohours and then poured into water. The solid that separated wascollected, air dried, and recrystallized twice from isopropyl alcohol,using decolorizing charcoal each time, and dried at C. and 20 mm. foreighteen hours to yield 39.7 g. of 1,6-bis(N-cyanomethyl-Z-piperidyl)hexane, M.P. 98101 C.

Analysis.Ca1cd. for C20H34N4Z N, 16.95. N, 16.96.

To 11.4 g. of lithium aluminum hydride was added 250 cc. oftetrahydrofuran; the mixture was stirred for thirty minutes; and then39.7 g. of 1,6-bis(N-cyanomethyl- 2-piperdyl)hexane dissolved in 350 cc.of tetrahydrofuran was added dropwise with stirring maintaining a slowreflux. After completion of the addition, the reaction mixture wasrefluxed gently on a steam bath for six and one half hour-s and thenallowed to stand at room temperature overnight. To the reaction mixturewas added 12 cc. of water dropwise with stirring, maintaining a slowreflux, followed by additionof cc. of a saturated solution of potassiumsodium tartrate added dropwise, maintaining the slow reflux. The mixturewas cooled in ice, filtered through infusorial earth and the filter aidwashed with tetrahydrofuran. The filtrate was evaporated to remove thesolvent, thereby yielding 38.8 g. of a yellow oily material. Thirtygrams of the oily material was distilled in vacuo yielding the followingfractions: (1) 1.3 g., n =1.5038, B.P. 116-138 C. at 0.15 m-m.; (2) 8.8g., n =1.5O25, B.P. 138-471 C. 'at 0.15 mm.; and (3) 13.2 g., n =1.5032,B.P. 171-173 C. These three fractions of 1,6-bis [N- 2-aminoethyl)-2-piperdyl] hexane, totaling 23.3 g., were combined and analyzed.

' Analysis.--Calcd. for C H N N, 16.54. Found: N, 16.37.

Following the above procedure for the preparation of1,6-bis[N-(2-dichloroacetamidoethyl) 2-piperidyl1-hexane butsubstituting for 1,6-bis[N(2-aminoethyl)-2- piperidyl1hexane molarequivalent quantities of Found:

1,3-bis- [N-( 2-aminoethyl) -2-piperidyl] propane,

1,8-bis [N- 2-aminoethyl) -2-piperidyl] octane,

1, 6 -bis [N- (3 -aminopropyl) -2-piperidyl] hexane,

1,6-bis [N- (4-arninobutyl) -3 -piperidyl] hexane,

1- [N- (2-aminoethyl) -2-piperidyl] -6- [N- (Z-aminoethyl) 3-piperidyl]hexane or 1,4-bis [N-( 6-aminohexyl) -2-piperidyl] butane,

the following compounds are prepared:

1,3-bis [N- (2-dichloroacetamidoethyl -2-piperidyl] propane,

1,8-bis [N- (2-dichloraceta-rnidoethyl) -2-piperidyl] octane,

1 ,6-bis [N- (3 -dichloroacetamidopropyl) -2-piperidy1] hexane,

1,6-bis [N- (4-dichloroacetamidobutyl) -3 -piperidy-l] hexane,

l-[N- 2-dichloroacetamidoethyl) -2-piperidyl] -6- [N- (2-dichloroacetamidoethyl -3 piperidyl] hexane or 1,4-bis [N-( 6-dichloroacetamidohexyl) -2-piperidyl] butane, respectively.

The above intermediate di-[N-(aminoalkyl)- piperidyl] alkanes areprepared by following the above-described two-step procedure for thepreparation of l,6-bis[N- Z-aminoethyl)-2-piperidyl]hexane andsubstituting in the first step, the appropriate di-(piperidyl)-alkanefor 1,6-bis (2-piperidyl)hexane and, for the compounds other than thedi-[N-(Z-aminoethyl)-piperidyl]-alkanes, the appropriate chloro(orbromo)-alkanenitrile for glycolonitrile, and preferably using anacid-acceptor, e.g., sodium hydroxide solution, to take up the hydrogenhalide formed by the reaction, and then, in the second step, reducingthe resulting di-(N-cyanoalkylpiperidyl)-alkane with lithium aluminumhydride. For example, 1,8-bis[N-(2-aminoethyl) -2-piperidyl]octane isformed by reacting 1,8-bis(2 piperidyl)octane with glycolonitrile andreducing the resultin g 1,8-bis [N- (cyanomethyl -2-piperidyl] octane;1,6- bis[N-(4-aminobutyl)-3-piperidyl]hexane is formed by reacting1,6-bis(3-piperidyl)hexane with 4-bromobutanenitrile('y-bromobutyronitrile) and reducing the resulting1,6-bis[N-(3-cyanopropyl)-3-piperidyl]hexane; and 1,4-bis[N-(6-aminohexyl)-2 piperidyl]butane is formed by reacting1,4-bis(2-piperidyl)butane' with 6-chlorohexanenitrile and reducing theresulting 1,4-bis[N-(5-cyanopentyl -2-piperidyl] butane.

Example 6 l,6-bis(N-trichloroacetyl-Z-piperidyl)hexane was preparedfollowing the procedure described in Example 2 using 10.2 g. ofl,6-bis(2-piperidyl)hexane in 100 cc. of ethylene dichloride, 18.1 g. oftrichloroacetyl chloride in 50 cc. of ethylene dichloride, and an excessof 10% aqueous sodium hydroxide solution. There was thus obtained 7.8 g.of the product, 1,6-bis(N-trichloroacetyl-2- piperidyl)hexane,'M.P.150.6152.0 C. (corn), after two recrystallizations from ethyl acetate.

Analysis.Calcd. for cgoHaoclsNzozi C, 44.22; H, 5.57; N, 5.16. Found: C,44.54; H, 5.78; N, 5.22.

l,6-bis(N-trichloroacetyI-Z-piperidyl)hexane when administered orally tohamsters infected with Endamoeba criceti was found to clear 5 out of 5of the animals at a dose level of 200 mg./kg./ day. Following the aboveprocedure but using a molar equivalent quantity of tribromoacetylchloride, 2,2,3-trichloropropanoyl chloride or 2,3,4-trichlorobutan0ylchloride in place .of trichloroacetyl chloride, the following compoundsare formed: 1,6-bis(N-tribromoacetyl-2-piperidyl hexane, 1,6-bis(N-2,2,3-trichloropropanoyLZ-piperidyl)hexane or1,6-bis(N-2,3,4-trichlorobutanoyl-Z-piperidyl)hexane, respectively.

The amebacidally active compounds of my invention, as illustrated .inthe foregoing examples, were administered orally in aqueous suspensionto the infected hamsters. They can also be administered in solid form,e.g., as tablets or in capsules, and option'ally'admixed withconventional excipients, e.g., starch, talc, and the like.

I claim:

1. A di-piperidine of the formula AC1 AC2 GUI-RUIN where Y is alkylenehaving from three to eight carbon atoms between its connecting linkages,X and X are each lower-alkylene having from two to six carbon atoms andhaving at least two carbon atoms between its connecting linkages, and,Ac and Ac are each halo-lower-alkanoyl having from one to four carbonatoms and from one to three halogen atoms.

8. 1,6-bis[N-(2-dichloroacetamidoethyl) Z-piperidyl] hexane.

No references cited- WALTER A. MODANCE, Primary Examiner. AVROM D.SPEVACK, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,277,101 October 4, 1966 Alexander R. Surrey It is hereby certifiedthat error appears in the above numbered patent requiring correction andthat the said Letters Patent should read as corrected below.

Column 2, line 15, for "diidoacetyl" read diiodoacetyl column 6, lines26 and 44, for "piperdyl", each occurrence,

for "2-aminoethyl)" read piperidyl column 7, line 2, read (2-aminoethyl)column 8, line 32, the left-hand portion of the formula should appear asshown below instead of as in the patent:

Signed and sealed this 12th day of September 1967.

(SEAL) Attest:

EDWARD J. BRENNER ERNEST W. SW'IDER Attesting Officer Commissioner ofPatents

1. A DI-PIPERIDINE OF THE FORMULA
 7. A DI-PIPERIDINE OF THE FORMULA